Ulk4, a Newly Discovered Susceptibility Gene for Schizophrenia, Regulates Corticogenesis in Mice.
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ABSTRACT:
SUBMITTER: Hu L
PROVIDER: S-EPMC8255617 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4 +/tm1a mice, demonstrating that Ulk4 +/tm1a mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4 +/tm1a mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67+ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4 +/tm1a mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments.
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Project description:The ULK (UNC51-like) enzymes are a family of mammalian kinases that have critical roles in autophagy and development. While ULK1, ULK2, and ULK3 have been characterized, very little is known about ULK4. However, recently, deletions in ULK4 have been genetically linked to increased susceptibility to developing schizophrenia, a devastating neuropsychiatric disease with high heritability but few genes identified. Interestingly, ULK4 is a pseudokinase with some unusual mutations in the kinase catalytic motifs. Here, we report the first structure of the human ULK4 kinase at high resolution and show that although ULK4 has no apparent phosphotransfer activity, it can strongly bind ATP. We find an unusual mechanism for binding ATP in a Mg2+-independent manner, including a rare hydrophobic bridge in the active site. In addition, we develop two assays for ATP binding to ULK4, perform a virtual and experimental screen to identify small-molecule binders of ULK4, and identify several novel scaffolds that bind ULK4 and can lead the way to more selective small molecules that may help shed light on the function of this enigmatic protein.
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